Intergenerational protective anti-gut commensal immunoglobulin G originates in early life.

Maternal immunoglobulins of the class G (IgGs) protect offspring from enteric infection, but when, where, and how these antibodies are physiologically generated and confer protection remains enigmatic. We found that circulating IgGs in adult mice preferentially bind early-life gut commensal bacteria over their own adult gut commensal bacteria. IgG-secreting plasma cells specific for early-life gut bacteria appear in the intestine soon after weaning, where they remain into adulthood. Manipulating exposure to gut bacteria or plasma cell development before, but not after, weaning reduced IgG-secreting plasma cells targeting early-life gut bacteria throughout life. Further, the development of this anti-gut commensal IgG response coincides with the early-life interval in which goblet cell-associated antigen passages (GAPs) are present in the colon. Offspring of dams "perturbed" by B cell ablation or reduced bacterial exposure in early life were more susceptible to enteric pathogen challenge. In contrast to current concepts, protective maternal IgGs targeted translocating gut commensals in the offspring, not the enteric pathogen. These early-life events affecting anti-commensal IgG production have intergenerational effects for protection of the offspring.

Exploring the determinants of successful implementation of a preventive mental health and wellness intervention for Afghan refugee families: a qualitative analysis.

Many refugee children experience trauma in early childhood. Effective, tailored interventions are needed to improve refugee children's access to preventive mental health. We interviewed refugee-serving stakeholders and parents participating in an evidence-based preventive mental health and wellness intervention adapted for Afghan refugee children and families who may have experienced trauma. Interview guide development was informed by two implementation science frameworks: the Consolidated Framework for Implementation Research and the Model for Adaptation Design and Impact. A three-person team coded transcripts via rapid qualitative analysis, and the study team reached consensus on themes. Six refugee-serving facilitators and five refugee parents discussed key determinants of successful implementation. Themes included: (i) modeling cultural humility to promote communication about emotions; (ii) needed linguistic support and referral networks to avoid miscommunications and missed communications; (iii) bridging connections between children, families and schools; (iv) different takeaways, or differing goals and expectations between facilitators and participants; and (v) timely, specific cultural considerations to overcome participation barriers. Overall, we found key determinants of successful implementation of a preventive mental health and wellness intervention for refugee children and families included adaptations to enhance cultural humility and sensitivity to cultural context while strengthening communication among facilitators, children and families.

Insulin Pump Utilization in 2017-2021 for More Than 22,000 Children and Adults With Type 1 Diabetes: A Multicenter Observational Study.

This large type 1 diabetes cohort study showed that insulin pump utilization has increased over time and that use differs by sex, insurance type, and race/ethnicity. Insulin pump use was associated with more optimal A1C, increased use of continuous glucose monitoring (CGM), and lower rates of diabetic ketoacidosis and severe hypoglycemia. People who used an insulin pump with CGM had lower rates of acute events than their counterparts who used an insulin pump without CGM. These findings highlight the need to improve access of diabetes technology through provider engagement, multidisciplinary approaches, and efforts to address health inequities.

The Development and Initial Validation of Items to Assess Parent Fear of Nighttime Hypoglycemia.

OBJECTIVE: Parents of youth with type 1 diabetes (T1D) are fearful their children will experience nighttime hypoglycemia. Currently, the Hypoglycemia Fear Survey for Parents (HFS-P) lacks items that specifically assess parents' nighttime fear. This study aimed to fill this gap by rigorously identifying new items to specifically assess parent fear of nighttime hypoglycemia and then examine the psychometric properties of the revised Hypoglycemia Fear Survey for Parents including Nighttime Fear (HFS-P-NF). METHODS: For Phase 1, we recruited 10 pediatric diabetes providers and 15 parents/caregivers of youth with T1D to generate items related to fear of nighttime hypoglycemia. For Phase 2, we recruited an additional 20 parents/caregivers to pilot-test the newly generated items. For Phase 3, we recruited another 165 parents/caregivers to evaluate structural validity via confirmatory factor analyses, reliability, and content validity of the revised HFS-P-NF. RESULTS: In Phase 1, we generated 54 items. In Phase 2, we removed 34 items due to violations of distributional normality and nonsignificant correlations. In Phase 3, a four-factor model reflecting behaviors maintaining high glucose, helplessness, negative social consequences, and nighttime worries was the best fitting model for the HFS-P-NF. The new items demonstrated strong internal consistency (α = 0.96) and strong to moderate relationships with criterion and content validity measures. CONCLUSION: The current study provides initial evidence of validity and reliability for new items on the HFS-P-NF that broadened the conceptualization of parent fear of nighttime hypoglycemia. These findings are important to clinicians who may consider screening for parent fear of nighttime hypoglycemia more comprehensively.

Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals. Objective: To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years. Interventions: Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo. Main Outcomes and Measures: The primary outcome was mixed-meal tolerance test-stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis. Results: Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, -0.01 [95% CI, -0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group. Conclusions and Relevance: In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes. Objective: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022. Interventions: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care. Main Outcomes and Measures: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. Results: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment. Conclusions and Relevance: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Factors Associated With Achieving Target A1C in Children and Adolescents With Type 1 Diabetes: Findings From the T1D Exchange Quality Improvement Collaborative.

The optimal care of type 1 diabetes involves consistent glycemic management to avoid short- and long-term complications. However, despite advancements in diabetes technology and standards, achieving adequate glycemic levels in children and adolescents remains a challenge. This study aimed to identify factors associated with achieving the recommended A1C target of <7% from the United States-based multicenter T1D Exchange Quality Improvement Collaborative cohort, including 25,383 children and adolescents living with type 1 diabetes.

Multi-Clinic Quality Improvement Initiative Increases Continuous Glucose Monitoring Use Among Adolescents and Young Adults With Type 1 Diabetes.

Continuous glucose monitoring (CGM) use is associated with improved A1C outcomes and quality of life in adolescents and young adults with diabetes; however, CGM uptake is low. This article reports on a quality improvement (QI) initiative of the T1D Exchange Quality Improvement Collaborative to increase CGM use among patients in this age-group. Ten centers participated in developing a key driver diagram and center-specific interventions that resulted in an increase in CGM use from 34 to 55% in adolescents and young adults over 19-22 months. Sites that performed QI tests of change and documented their interventions had the highest increases in CGM uptake, demonstrating that QI methodology and sharing of learnings can increase CGM uptake.

Inequities in Health Outcomes in Children and Adults With Type 1 Diabetes: Data From the T1D Exchange Quality Improvement Collaborative.

Health care inequities among racial and ethnic groups remain prevalent. For people with type 1 diabetes who require increased medical access and care, disparities are seen in access to care and health outcomes. This article reports on a study by the T1D Exchange Quality Improvement Collaborative evaluating differences in A1C, diabetic ketoacidosis (DKA), severe hypoglycemia, and technology use among racial and ethnic groups. In a diverse cohort of nearly 20,000 children and adults with type 1 diabetes, A1C was found to differ significantly among racial and ethnic groups. Non-Hispanic Blacks had higher rates of DKA and severe hypoglycemia and the lowest rate of technology use. These results underscore the crucial need to study and overcome the barriers that lead to inequities in the care and outcomes of people with type 1 diabetes.

Effect of plasma processing and storage on microparticle abundance, nitric oxide scavenging, and vasoactivity.

BACKGROUND: We set out to define the impact of collection, processing, and storage on plasma product microparticle (MP) abundance, potential for nitric oxide (NO) scavenging, and vasoactivity. STUDY DESIGN AND METHODS: Three currently US licensed products were tested: liquid plasma (LP), fresh frozen plasma (FFP), and solvent detergent plasma (SDP), along with a product under development, spray-dried solvent detergent plasma (SD-SDP) with/without beads. Vasoactivity was assessed in vitro using rabbit aortic vascular rings; MP abundance was determined by flow cytometry; and NO scavenging capacity/rate was determined using a biochemical NO consumption assay. All samples were analyzed unprocessed and following centrifugation at two speeds (2,500× g to remove platelets, and 25,000× g to remove microparticles). RESULTS: Significant differences in vasoactivity were observed, with SD-SDP minus beads demonstrating the greatest constriction and FFP the lowest constriction response. All products exhibited the same total NO scavenging capacity; however, significant differences were observed in the maximal rate of scavenging, with SD-SDP minus beads and FFP reacting fastest and SDP the slowest. Across all products, platelet and microparticle depletion had no effect on vasoactivity or NO scavenging (total or rate). Microparticles (RBC derived) were found only in FFP and LP, with relative abundance (LP > FFP). Additionally, storage had no effect on total or RBC-derived MP abundance, NO scavenging, or vasoactivity. CONCLUSION: Although vasoactivity differed between plasma products, we did not find similar differences in either total or RBC-derived MP abundance or NO scavenging capacity/rate.

Sleep and type 1 diabetes in children and adolescents: Proposed theoretical model and clinical implications.

Youth with type 1 diabetes mellitus (T1D) experience more sleep disturbances and shorter sleep durations compared to their healthy peers. Researchers have now uncovered the negative mental health and physical health outcomes associated with poor sleep in youth with T1D. The field of T1D sleep research currently operates under the broad notion that sleep behaviors impact treatment adherence, which ultimately lead to worse long-term health outcomes. This model however does not explain how behavior influences T1D management and sleep outcomes on a day-to-day basis, leading to difficulties in providing tailored treatment recommendations. In this review, we present a theoretical framework that describes the recursive cycle between sleep behaviors, T1D outcomes, and symptoms of negative affect/stress over a 24-hour period. This model is guided by the sleep literature, showing a clear relationship between poor sleep and negative affect, and the T1D literature demonstrating a link between poor sleep and disease management for youth with T1D. Further, emerging literature indicates a need for additional parent sleep assessment considering that T1D management and fear of hypoglycemia negatively impact parent sleep behaviors. Recommendations are provided to move the field toward effective intervention studies and new areas of research to evaluate and modify the proposed model.

Implementing clinic-wide depression screening for pediatric diabetes: An initiative to improve healthcare processes.

OBJECTIVE: Youth with type 1 diabetes (T1D) endorse high rates of depressive symptoms, which can significantly impair self-management, glycemic control, and quality of life. Current guidelines recommend annual depression screening for all adolescents with T1D, but few models exist to implement screening procedures across clinics in this population. The primary aim of this project was to increase depression screening from 0% to 80% in four clinics, and to describe the structured quality improvement process to reach this goal. METHODS: All patients aged 12 to 21 years old with T1D at four participating clinics in a Midwestern hospital system were eligible to participate. Using a two-stage process, patients were administered the Patient Health Questionnaire (PHQ-2 plus PHQ-9 if positive) annually. Rates of depression screening by clinic site, rates of positive depression screens, social worker documentation of follow-up care, and associations with diabetes-related health outcomes were analyzed. RESULTS: Over 2 years, average depression screening rates increased from 0% to 75% across all clinics, and 89% of patients with a positive screen met with a social worker for a targeted mental health assessment. At initial screening, 7.6% of patients screened positive for at-risk depressive symptoms on the PHQ-2 and from that group, 6.7% additionally screened positive on the PHQ-9. CONCLUSIONS: Annual depression screenings were feasibly implemented across four clinics and the use of real-time data listening and automated processes facilitated successful implementation. Future directions include further automation, targeted training and billing mechanisms, dissemination to non-metropolitan clinics, and further assessment of depression screening tools for adolescents with T1D.

Sleep duration and its impact on adherence in adolescents with type 1 diabetes mellitus.

BACKGROUND: Adherence to the type 1 diabetes (T1D) regimen, while predictive of glycemic control, decreases during adolescence. For adolescents, attaining adequate sleep is an additional challenge. This study evaluates the impact of sleep on adherence in teens with T1D. SUBJECTS: Forty-five adolescents aged 12-18 yr, with T1D for at least 6 months while on insulin pump therapy. METHODS: Adolescents logged their sleep on a written diary for 2 wk. Corresponding insulin pump/glucometer downloads as well as sleep habit questionnaires were also obtained. RESULTS: Data from 20 girls and 25 boys, with a mean age of 15 ± 1.6 yr and mean glycated hemoglobin of 8.7 ± 1.1% (72 mmol/mol), were analyzed. Overall, average sleep was 8.6 ± 0.9 h per night. Sleep durations were compared to the next day's frequency of self-monitored blood glucose (SMBG) and total daily insulin bolus frequency. Associations were found between sleep duration and youths' SMBG and insulin bolus frequencies (p < 0.03 and p < 0.001, respectively). Specifically, a 15- and 20-min increase in sleep was associated with one additional SMBG check and one additional insulin bolus, respectively. CONCLUSION: Analyses suggest an associated increase in T1D self-management behaviors in youths with increased sleep duration. These findings highlight the importance of assessing sleep in clinical practice, and encourage further research to examine effective strategies to address sleep hygiene as part of routine diabetes management.

Management of diabetic ketoacidosis in children: Does early insulin glargine help improve outcomes?

BACKGROUND: Rebound hyperglycemia following the resolution of diabetic ketoacidosis (DKA) is common in pediatric patients with type 1 diabetes, increasing the risk of recurrent DKA and complicating the transition to subcutaneous insulin. Multiple studies suggest that early administration of long-acting insulin analogs during DKA management safely improves this transition. OBJECTIVE: This study aimed to determine whether early insulin glargine administration in children with DKA prevents rebound hyperglycemia and recurrent ketosis without increasing the rate of hypoglycemia or hypokalemia. METHODS: Patients aged <21 years presenting with DKA to Children's Mercy Kansas City between October 2012 and October 2016 were reviewed. They were categorized as Early (>4 h of overlap with intravenous [IV] insulin) and Late (<2 h of overlap) cohorts. RESULTS: We reviewed 546 DKA admissions (365 Early and 181 Late). Rebound hyperglycemia (>180 mg/dL) was lower in the Early group (66% vs. 85%, p ≤ 0.0001). Hypoglycemia (<70 mg/dL) during IV insulin administration was higher in the Early group than in the Late group (27% vs. 19%, p = 0.042). Hypoglycemia within 12 h of IV insulin discontinuation was lower in the Early group (16% vs. 26%, p = 0.012). Recurrent ketosis, hypokalemia, and cerebral edema were not different between the groups. CONCLUSIONS: Early glargine administration in pediatric DKA management is safe, decreases the rate of rebound hyperglycemia, and improves the transition to subcutaneous insulin. Hypoglycemia is less frequent following IV insulin discontinuation with early glargine, but the IV insulin rate may need to be reduced to minimize hypoglycemia during IV insulin infusion.

The Design of the Electronic Health Record in Type 1 Diabetes Centers: Implications for Metrics and Data Availability for a Quality Collaborative.

BACKGROUND: Systematic and comprehensive data acquisition from the electronic health record (EHR) is critical to the quality of data used to improve patient care. We described EHR tools, workflows, and data elements that contribute to core quality metrics in the Type 1 Diabetes Exchange Quality Improvement Collaborative (T1DX-QI). METHOD: We conducted interviews with quality improvement (QI) representatives at 13 T1DX-QI centers about their EHR tools, clinic workflows, and data elements. RESULTS: All centers had access to structured data tools, nine had access to patient questionnaires and two had integration with a device platform. There was significant variability in EHR tools, workflows, and data elements, thus the number of available metrics per center ranged from four to 17 at each site. Thirteen centers had information about glycemic outcomes and diabetes technology use. Seven centers had measurements of additional self-management behaviors. Centers captured patient-reported outcomes including social determinants of health (n = 9), depression (n = 11), transition to adult care (n = 7), and diabetes distress (n = 3). Various stakeholders captured data including health care professionals, educators, medical assistants, and QI coordinators. Centers that had a paired staffing model in clinic encounters distributed the burden of data capture across the health care team and was associated with a higher number of available data elements. CONCLUSIONS: The lack of standardization in EHR tools, workflows, and data elements captured resulted in variability in available metrics across centers. Further work is needed to support measurement and subsequent improvement in quality of care for individuals with type 1 diabetes.

The breath volatilome is shaped by the gut microbiota.

The gut microbiota is widely implicated in host health and disease, inspiring translational efforts to implement our growing body of knowledge in clinical settings. However, the need to characterize gut microbiota by its genomic content limits the feasibility of rapid, point-of-care diagnostics. The microbiota produces a diverse array of xenobiotic metabolites that disseminate into tissues, including volatile organic compounds (VOCs) that may be excreted in breath. We hypothesize that breath contains gut microbe-derived VOCs that inform the composition and metabolic state of the microbiota. To explore this idea, we compared the breath volatilome and fecal gut microbiomes of 27 healthy children and found that breath VOC composition is correlated with gut microbiomes. To experimentally interrogate this finding, we devised a method for capturing exhaled breath from gnotobiotic mice. Breath volatiles are then profiled by gas-chromatography mass-spectrometry (GC-MS). Using this novel methodology, we found that the murine breath profile is markedly shaped by the composition of the gut microbiota. We also find that VOCs produced by gut microbes in pure culture can be identified in vivo in the breath of mice monocolonized with the same bacteria. Altogether, our studies identify microbe-derived VOCs excreted in breath and support a mechanism by which gut bacterial metabolism directly contributes to the mammalian breath VOC profiles.

Novel expansion of a well-established antimicrobial stewardship program: Enhancing program efficiency and reach.

OBJECTIVE: To evaluate efficiency and impact of a novel antimicrobial stewardship program (ASP) prospective-audit-with-feedback (PAF) review process using the Cerner Multi-Patient Task List (MPTL). DESIGN: Retrospective cohort study. SETTING: A 367-bed free-standing, pediatric academic medical center. METHODS: The ASP PAF review process expanded to monitor all systemic and inhaled antibiotics through use of the MPTL on July 23, 2020. Average number of daily ASP reviews, absolute number of monthly interventions, and time to conduct ASP reviews were compared between the preimplementation period and the postimplementation period following expansion. Antibiotic days of therapy (DOT) per 1,000 patient days for overall and select antibiotics were compared between periods. ASP intervention characteristics were assessed. RESULTS: Average daily ASP reviews significantly increased following program expansion (9 vs 14 reviews; P < .0001), and the absolute number of ASP interventions each month also increased (34 vs 52 interventions; P ≤ .0001). Time to conduct daily ASP reviews increased in the postimplementation period (1.03 vs 1.32 hours). Overall antibiotic DOT per 1,000 patient days significantly decreased in the postimplementation period (457.9 vs 427.9; P < .0001) as well as utilization of select, narrow-spectrum antibiotics such as ampicillin and clindamycin. Intervention type and antibiotics were similar between periods. The ASP documented 128 "nonantibiotic interventions" in the postimplementation period, including culture and/or susceptibility testing (32.8%), immunizations (25.8%), and additional diagnostic testing (22.7%). CONCLUSIONS: Implementation of an ASP PAF review process using the MPTL allowed for efficient expansion of a pre-existing ASP and a decrease in overall antibiotic utilization. ASP documentation was enhanced to fully track the impact of the program.

The gut microbiota of people with asthma influences lung inflammation in gnotobiotic mice.

The gut microbiota in early childhood is linked to asthma risk, but may continue to affect older patients with asthma. Here, we profile the gut microbiota of 38 children (19 asthma, median age 8) and 57 adults (17 asthma, median age 28) by 16S rRNA sequencing and find individuals with asthma harbored compositional differences from healthy controls in both adults and children. We develop a model to aid the design of mechanistic experiments in gnotobiotic mice and show enterotoxigenic Bacteroides fragilis (ETBF) is more prevalent in the gut microbiota of patients with asthma compared to healthy controls. In mice, ETBF, modulated by community context, can increase oxidative stress in the lungs during allergic airway inflammation (AAI). Our results provide evidence that ETBF affects the phenotype of airway inflammation in a subset of patients with asthma which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.